Abstract-Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) present in fish oils have been ascribed as having significant antithrombotic and antiatherosclerotic effects. Vascular smooth muscle cell (SMC) proliferation plays an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have indicated that serotonin at concentrations present at sites of vascular injury stimulates SMC proliferation and may contribute to the restenotic process. In the present study we demonstrate that among the fatty acids tested, only EPA and DHA could block the mitogenic effect of serotonin on vascular SMC. Further, when added together these fatty acids act synergistically in blocking the mitogenic effect of serotonin. EPA and DHA blocked the 5HT-induced increase in the 5-HT 2 receptor mRNA. This antimitogenic effect of EPA and DHA may partially explain some of the beneficial effects of fish oils. Key Words: smooth muscle cell Ⅲ eicosapentaenoic acid Ⅲ docosahexaenoic acid Ⅲ serotonin Ⅲ restenosis C oronary events appear to be less frequent among populations consuming large amounts of 3 polyunsaturated fatty acids (fish oils). 1,2 Clinical trials involving survivors of acute myocardial infarction have demonstrated a reduction in subsequent coronary events through an increase in the consumption of fish 3 or ␥-linoleic acid, a precursor of 3 fatty acids derived from vegetable sources. 4 However, the exact mechanism(s) of action of these complex heterogeneous compounds remain incompletely characterized. Among the diverse biological effects of 3 fatty acids, favorable alteration of lipoprotein levels, changes in eicosanoid metabolism, and inhibition of platelet aggregation have been implicated in the prevention of atherosclerosis. 5-8 Dietary 3 fatty acids have also been shown to reduce experimental vascular lesion formation in dogs, 9,10 swine, 11,12 rabbits, 13,14 and nonhuman primates. 15,16 Yet the results of dietary 3 fatty acids on restenosis in patients undergoing coronary angioplasty have been inconclusive. 17,18 Restenosis after coronary angioplasty involves intimal proliferation of vascular smooth muscle cell (SMC), probably in response to mitogens released from aggregating platelets as well as from monocyte-derived macrophages that accumulate at the site of vascular injury. Platelets contain peptide growth factors like platelet derived growth factor (PDGF), epidermal growth factor (EGF), and transforming growth factor-, 19 -21 and nonpeptide vasoactive compounds like serotonin (5HT), thromboxane A 2 , (TXA 2 ), norepinephrine, histamine, bradykinin, and platelet activating factor. 22,23 Recent studies from our laboratory and those of others indicate that some of these vasoactive compounds like 5HT and TXA 2 are also mitogens to vascular SMC in culture, 22,24 -26 which suggests that vasoactive compounds may play an important role in the development of neointima. In the present study we investigated the putative mechanism by which eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic a...